Ibuprofen, or 2-(4-isobutylphenyl)propanoic acid, is a member of the propionic acid group of non-steroidal anti-inflammatory drugs (“NSAIDs”). Ibuprofen was originally marketed in oral form as Brufen™, and since then under various other trademarks, including Nurofen™, Advil™ and Motrin™. Ibuprofen is used for relief of symptoms of arthritis, primary dysmenorrheal, fever and as an analgesic, especially where there is an inflammatory component.
Ibuprofen occurs as [+]S- and [−]R-enantiomers and as a racemic mixture of the two. It is a white to off-white crystalline powder, practically insoluble in water (<0.1 mg/mL), but readily soluble in polar organic solvents such as ethanol and acetone.
Current topical formulations of ibuprofen that are available include, for example, Ibugel™, Ibuleve™ (5% ibuprofen gel), Deep Relief™ Dual Action Gel (5% ibuprofen, 3% levomenthol gel), Nurofen™ (10% ibuprofen gel), Booths Ibuprofen Gel (5% ibuprofen gel) and Sainsbury's Ibuprofen Pain Relief Gel (10% ibuprofen gel).
Various factors can affect the absorption rates and penetration depth of topical pharmaceutical preparations, including the nature of the active ingredient, the nature of the vehicle, the pH, and the relative solubility of the active in the vehicle versus the skin [Ostrenga J. et al., Significance of vehicle composition I: relationship between topical vehicle composition, skin penetrability, and clinical efficacy, Journal of Pharmaceutical Sciences, 60: 1175-1179 (1971)]. More specifically, drug attributes such as solubility, particle size and charge, as well as vehicle attributes such as the drug dissolution rate, spreadability, adhesion, and ability to alter membrane permeability can each have significant effects on penetration.
Seemingly minor variations in formulations can produce significant changes in their performance. For instance, Naito et al. demonstrates significant variability in penetration among topical NSAID formulations simply by changing the gelling agent used in the compositions [Naito et al., Percutaneous absorption of diclofenac sodium ointment, Int. Jour. of Pharmaceutics, 24: 115-124 (1985)]. Similarly, Ho noted significant variability in penetration by changing the proportions of alcohol, propylene glycol, and water [Ho et al., The influence of cosolvents on the in-vitro percutaneous penetration of diclofenac sodium from a gel system, [J. Pharm. Pharmacol., 46:636-642 (1994)]. It was noted that the changes affected three distinct variables: (i) the solubility of the drug in the vehicle, (ii) the partition coefficient of the drug between the vehicle and the skin, and (iii) the alteration of skin structure [Id.].
Ho et al. also noted that (i) the pH of the vehicle, (ii) the drug solubility, and (iii) the viscosity of a gel matrix can influence penetration from a gel dosage form [Id.]. The pH value affects the balance between the ionized and non-ionized forms of the drug, which typically have different permeation properties [Obata, International Journal of Pharmaceutics, 89: 191-198 (1993)]. The viscosity can affect diffusion of the drug through the gel matrix and release of the drug from the vehicle into the skin. The solubility of the drug in the vehicle will affect the partition coefficient of the drug between the composition and the recipient membrane or tissue [Ho, Id.].
The skin barrier can be compromised by several physical methods, such as iontophoresis, ultrasound, electroporation, heat, and microneedles. Molecular penetration enhancers (MPE™s) are a preferred means for reversibly reducing the skin barrier. At least 400 chemicals have been identified as skin permeability enhancers. General categories of MPE™s include pyrrolidones, fatty acids, fatty acid esters, fatty acid alcohols, sulfoxides, essential oils, terpenes, oxazolidines, surfactants, polyols, azone and derivatives, and epidermal enzymes.
The mechanisms by which MPE™s reduce the skin barrier function are not well understood [see Williams and Barry “Penetration Enhancers” Advanced Drug Delivery Reviews 56: 603-618 (2004)], although it has been proposed that the mechanisms can be grouped into three broad categories: lipid disruption, increasing corneocyte permeability, and promoting partitioning of the drug into the tissue.
The challenge with use of MPE™s is that few seem to induce a significant or therapeutic enhancement of drug transport at tolerable levels. This is because an MPE™'s disruption of the skin barrier can potentially cause skin irritation, damage or both. With increased disruption, skin irritation is expected to become a greater issue. This is particularly problematic with topical pain treatments where the goal is to have the active penetrate deeply into the underlying tissue or where the drug must be used on a long-term basis due to the nature of the pain.
In light of the foregoing, there is a considerable need for the development of topical ibuprofen formulations suitable for use in the treatment of pain. The challenge has been to develop an optimal composition which will deliver the active agent to the underlying tissue in sufficient concentration to treat pain, while reducing or minimizing the incidence of skin irritation caused by disrupting the skin barrier and while providing a composition and dosage that leads to and encourages patient compliance.